rs2303729

Variant names:

• chr19-40605163-G-A
• rs2303729
• NM_001042545.2:c.379G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042545.2(LTBP4):​c.379G>A​(p.Val127Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,609,426 control chromosomes in the GnomAD database, including 171,420 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.51 (20449 hom., cov: 32)
  • Exomes 𝑓: 0.45 (150971 hom.)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.185
• Publications: 64 publications found

Genes affected

LTBP4 (HGNC:6717): (latent transforming growth factor beta binding protein 4) The protein encoded by this gene binds transforming growth factor beta (TGFB) as it is secreted and targeted to the extracellular matrix. TGFB is biologically latent after secretion and insertion into the extracellular matrix, and sheds TGFB and other proteins upon activation. Defects in this gene may be a cause of cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

LTBP4 Gene-Disease associations (from GenCC):

• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2299933E-5).
• BP6: Variant 19-40605163-G-A is Benign according to our data. Variant chr19-40605163-G-A is described in ClinVar as Benign. ClinVar VariationId is 163945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042545.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	NM_001042545.2	MANE Select	c.379G>A	p.Val127Ile	missense	Exon 2 of 30	NP_001036010.1	Q8N2S1-2
	LTBP4	NM_001042544.1		c.580G>A	p.Val194Ile	missense	Exon 5 of 33	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.469G>A	p.Val157Ile	missense	Exon 5 of 33	NP_003564.2	B3KXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.379G>A	p.Val127Ile	missense	Exon 2 of 30	ENSP00000380031.5	Q8N2S1-2
	LTBP4	ENST00000308370.11	TSL:1	c.580G>A	p.Val194Ile	missense	Exon 5 of 33	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.469G>A	p.Val157Ile	missense	Exon 5 of 33	ENSP00000204005.10	A0A0C4DH07

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76876 AN: 151908 Hom.: 20415 Cov.: 32

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.473

GnomAD2 exomes AF: 0.461 AC: 110943 AN: 240400 AF XY: 0.468

Gnomad AFR exome AF: 0.671

Gnomad AMR exome AF: 0.311

Gnomad ASJ exome AF: 0.581

Gnomad EAS exome AF: 0.419

Gnomad FIN exome AF: 0.483

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.453

GnomAD4 exome AF: 0.451 AC: 657856 AN: 1457400 Hom.: 150971 Cov.: 60 AF XY: 0.456 AC XY: 330487 AN XY: 724720

African (AFR) AF: 0.678 AC: 22662 AN: 33412

American (AMR) AF: 0.319 AC: 14041 AN: 44016

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 14975 AN: 26032

East Asian (EAS) AF: 0.371 AC: 14651 AN: 39528

South Asian (SAS) AF: 0.557 AC: 47734 AN: 85720

European-Finnish (FIN) AF: 0.486 AC: 25607 AN: 52710

Middle Eastern (MID) AF: 0.503 AC: 2895 AN: 5756

European-Non Finnish (NFE) AF: 0.438 AC: 486524 AN: 1110032

Other (OTH) AF: 0.478 AC: 28767 AN: 60194

GnomAD4 genome AF: 0.506 AC: 76965 AN: 152026 Hom.: 20449 Cov.: 32 AF XY: 0.506 AC XY: 37592 AN XY: 74296

African (AFR) AF: 0.664 AC: 27548 AN: 41482

American (AMR) AF: 0.381 AC: 5822 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2024 AN: 3470

East Asian (EAS) AF: 0.402 AC: 2074 AN: 5164

South Asian (SAS) AF: 0.554 AC: 2667 AN: 4816

European-Finnish (FIN) AF: 0.495 AC: 5227 AN: 10564

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.443 AC: 30122 AN: 67940

Other (OTH) AF: 0.472 AC: 993 AN: 2102

Alfa AF: 0.457 Hom.: 56812

Bravo AF: 0.502

TwinsUK AF: 0.442 AC: 1638

ALSPAC AF: 0.436 AC: 1682

ESP6500AA AF: 0.660 AC: 2543

ESP6500EA AF: 0.454 AC: 3739

ExAC AF: 0.465 AC: 56062

Asia WGS AF: 0.495 AC: 1722 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (4)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.000012	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.18
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.17
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.046
MPC		0.66
ClinPred		0.0061	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.063
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2303729; hg19: chr19-41111069; COSMIC: COSV52589366; COSMIC: COSV52589366;